title: Excretion and metabolism of the antihypertensive agent, RWJ-26240 (McN-5691) in dogs.
abstract: The excretion and metabolism of a 2-ethynylbenzenealkanamine analog, antihypertensive RWJ-26240 (McN-5691), in beagle dogs was investigated. Recoveries of total radioactivity in urine and feces in the 7 days after oral administration of 14C-RWJ-26240 (6 mg/kg dose) were 2.8% and 96.8% of the radioactive dose, respectively. Representative plasma, urine, and fecal samples were pooled and purified for metabolite profiling, isolation, and identification. Unchanged RWJ-26240 (<19% of the dose) plus 12 metabolites were isolated and identified from these samples using chromatography (TLC, HPLC), spectroscopy (NMR, MS), and derivatization techniques. Unchanged RWJ-26240 plus identified metabolites accounted for >75% of the sample radioactivity in plasma and feces. The formation of RWJ-26240 metabolites can be depicted by the following proposed pathways: 1) N-demethylation, 2) O-demethylation, 3) phenyl hydroxylation, and 4) N-dealkylation. The first three pathways appeared to be quantitatively important steps which led to the production of four major metabolites (each >5% of the sample radioactivity). RWJ-26240 was extensively metabolized in the dog, and fecal excretion was the major route of elimination of RWJ-26240 and its metabolites.
authors.affiliation: Department of Drug Metabolism, The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
authors.forename: W N
authors.initials: WN
authors.lastname: Wu
authors.forename: J A
authors.initials: JA
authors.lastname: Masucci
authors.forename: G W
authors.initials: GW
authors.lastname: Caldwell
authors.forename: J R
authors.initials: JR
authors.lastname: Carson
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism; D001711:Biotransformation; D002121:Calcium Channel Blockers / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D008658:Inactivation, Metabolic / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D011437:Propylamines / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D002250:Carbon Radioisotopes; D011437:Propylamines; C055896:McN 5691